Posted on
Monday 21 November 2016

The presidential election is finally over and I want to get back to where I left off last month in the post in polite company… when I said:

Articles like these are part of a great big wake-up call, and I’m not sure they’re reaching the right audience in the right ways. For the moment, I’ll just add them to the growing catalog, and pick back up next week after the national election is behind us. Right now, diversion time – World Series, Game 7!

Objective: To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder.

…

Conclusions: Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence.

But in the ensuing several weeks, Peter C. Gøtzsche and others added yet a second study to the one mentioned above. This one is an analysis of some unpublished studies from a 2001-2002 EMA submission of Duloxetine for stress urinary incontinence [that was not approved]:

Background: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence.

Methods: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine [involving a total of 1913 patients] submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports [totalling 6870 pages and including individual patient data] to assess benefits [including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating] and harms {both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]}.

Results: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes [mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%] and change in Incontinence Quality of Life total score [mean difference 3.24, 95% CI 2.00 to 4.48]. However, the effect sizes were small, and a sensitivity analysis [with removal of one trial] showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 [95% CI 6 to 13]. The numbers needed to harm were 7 [95% CI 6 to 8] for discontinuing because of an adverse event and 7 [95% CI 6 to 9] for experiencing an activation event. No suicidality, violence or akathisia events were noted.

Interpretation: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.

[truncated from the original]

The two papers combined report seventeen blinded clinical trials [scattered over 28 years] with some ~1300 non-depressed subjects on SSRI/SNRI drugs compared with ~1200 placebo controls. The findings of an increased signal for suicidality with these drugs have been traditionally discounted by critics with various rationales because the medications are being given to depressed people [who are suicide-prone anyway]. So here’s a large cohort of studied patients where that explanation obviously won’t fly. And in each case, the forest plots still show that the target adverse events are significantly more prevalent in the drug treatment group than in the placebo controls. The question then becomes, "What were those target Adverse Events?"

And what of the numerous and compelling case histories of suicide, homicide, violence, agitation in some people taking SSRIs/SNRIs? They are often discounted as "anecdotes" – lacking the statistical/mathematical certifcation that comes from clinical trials. They are infrequent and just don’t show up with strong signals in RCTs or population studies. So these meta-analyses are attempts at quantifying the phenomena. But again, the question becomes, "What were those target Adverse Events?" "What do they mean by precursors to suicidality?"

Here are the criteria they used in searching through the articles/reports in these meta-analyses:

[Bielefeldt et al]

[Maund et al]

In the Bielfield et al [healthy volunteers] paper, they report on "suicidal or violent events or precursors to such events" without breaking them down. And in Maund et al [duloxetine in stress incontinence] they do break them down [above]. In this latter study they mention that there were no suicidal or violent events reported in these trials [it’s worth taking a look at this paper for the suicidal info that wasn’t reported].

In the course of a randomised double-blind crossover study comparing the effects of reboxetine and sertraline in a group of healthy volunteers, two volunteers became suicidal on sertraline. This paper describes the characteristics of the reactions experienced by both subjects. These problems were associated with a combination of akathisia and disinhihition. Dysphoric or akathisic responses on their own to either drug did not lead to suicidality in this group of subjects.

The Bielefeldt et al paper mentions a suicide in a healthy volunteer in a Duloxetine Trial that wasn’t included in these meta-analyses:

"In one of the two crossover trials we excluded because we did not have data on the first period separately, a healthy volunteer committed suicide, which was mentioned in both published articles. She had received duloxetine in increasing doses for 16 days, tapered off the maximum dose of 400 mg daily very quickly [in just four days according to the design of the study] and killed herself four days later while on placebo. The authors, several of whom were employees of Eli Lilly or owned stock in the company, judged her suicide lto be unrelated to study drug treatment, although it is well known that the suicide risk is high when an antidepressant is stopped abruptly…

If there’s an area where more has been written about a single controversy than the question of suicidality/akathisia as an adverse effect of the SSRI/SNRI medications, I don’t know what it would be. Prozac was introduced in 1987, and by 1990, the issue of suicidality was soon on the front burner…

In 1990, Teicher and colleagues reported on the emergence of suicidality on fluoxetine in a group of six patients. These reports were followed-up by reports from King et al., Creaney et al. , Rothschild and Locke and Wirshing et al., among others, reporting other cases where suicidality appeared to emerge in individuals taking fluoxetine.

from Healy2000

… where it continues to simmer to this day with a history too long to even think about summarizing. These two meta-analyses approach one of the lingering controversies, "Can these drugs cause the Akathisia syndrome, a precursor of violence and suicidality, in normal non-depressed people." But one can almost hear the critics in the background saying, "Wait a minute. There’s no suicides, suicidality, or violence in any of these trials. You mean to say thatactivation, agitation, akathisia, or agitaare enough for you to extrapolate forward to say they are precursors to suicide or violence? Where’s your evidence!?" And the believer might come back with, "Have you looked at all the case histories posted onSSRIstories[see alsoThe Story of SSRI Stories] and elsewhere!?" And in another version, this kind of back and forth has gone on with the black box warnings of suicidality on all antidepressants since 2004 almost ad infinitum. What’s a practicing physician to take from all 29 years [2016 – 1987 = 29] of these dueling reports and studies?

Posted on
Thursday 17 November 2016

The classic Psychologist laboratory animal study involves genetically identical rats living in cages divided into two groups – one control group and one with some experimental intervention. Blinded observations of some pre-defined outcome parameter are recorded and the groups compared statistically at the end of the study. By making everything about the groups exactly the same, you can reasonably conclude that any differences in the outcome parameters are caused by the intervention. In another variation, one might have a single group with a control period of observations, then a second period making the intervention – comparing the control period to the experimental period. Whatever the case, the point is to aim for uniform groups with the only difference being the intervention – control vs experimental.

And then there are the Ethologists who do just the opposite. They often try not to interfere or make their presence known at all. So they sit in trees in the jungle and watch the animals in their natural habitat [or even become a part of it eg Dian Fossey]. Their books tend to be about one individual or a small group – more like a case study or a family study. And the tables, graphs, and statistics aren’t so prominent as they are in the works of the laboratory based scientists. They’re replaced by narrative descriptions.

Scientific research and reasoning continually pass through the phases of the well-known empirical-scientific cycle of thought: observation – induction – deduction – testing [observe – guess – predict – check]. The use of statistical tests is of course first and foremost suited for “testing”, i.e., the fourth phase. In this phase one assesses whether certain consequences [predictions], derived from one or more precisely postulated hypotheses, come to pass. It is essential that these hypotheses have been precisely formulated and that the details of the testing procedure [which should be as objective as possible] have been registered in advance. This style of research, characteristic for the [third and] fourth phase of the cycle, we call hypothesis testing research.

This should be distinguished from a different type of research, which is common especially in [Dutch] psychology and which sometimes also uses statistical tests, namely material-exploration. Although assumptions and hypotheses, or at least expectations about the associations that may be present in the data, play a role here as well, the material has not been obtained specifically and has not been processed specifically as concerns the testing of one or more hypotheses that have been precisely postulated in advance. Instead, the attitude of the researcher is: “This is interesting material; let us see what we can find.” With this attitude one tries to trace associations [e.g., validities]; possible differences between subgroups, and the like. The general intention, i.e. the research topic, was probably determined beforehand, but applicable processing steps are in many respects subject to ad-hoc decisions. Perhaps qualitative data are judged, categorized, coded, and perhaps scaled; differences between classes are decided upon “as suitable as possible”; perhaps different scoring methods are tried along-side each other; and also the selection of the associations that are researched and tested for significance happens partly ad-hoc, depending on whether “something appears to be there”, connected to the interpretation or extension of data that have already been processed.

When we pit the two types so sharply against each other it is not difficult to see that the second type has a character completely different from the first: it does not so much serve the testing of hypotheses as it serves hypothesis-generation, perhaps theory-generation — or perhaps only the interpretation of the available material itself.

Although we can never achieve the uniformity of subjects or conditions as with the lab rats, we do use the Hypothesis Testing [lab rat] model for our Clinical Trials of medications. It makes sense given what we’re trying to find out – "Does this molecule have medicinal properties in the defined condition?" Usually, I bring up de Groot to emphasize the absolute necessity for preregistration ["It is essential that these hypotheses have been precisely formulated and thatthe details of the testing procedure … have been registered in advance"] – a point that cannot be emphasized too much given the ubiquity of "outcome switching" in clinical trial reports. This time, however, I’m bringing it up for a different reason. While the Clinical Trial method gives us a powerful tool for evaluating a medication’s effects, clinical medicine is a different story. Practicing physicians don’t see groups. We see one patient at a time, and our experience is more like a long series of case studies than a Randomized Clinical Trial – a string of anecdotes stretching from medical school to the present. And those adverse events mumbled at the end of Direct-to-Consumer ads are a haunting reality to be reckoned with.

An Anecdote: A young pregnant woman presented to the ER of our UK military hospital one evening with a severe URI and sore throat. She was given symptomatic medications and started on penicillin. The next day [a Sunday], she returned with a skin rash thought to be a reaction to the penicillin, and it was stopped. By Monday when she returned, the rash covered her body and she was admitted with a diagnosis of Stevens-Johnson Syndrome. We had two Internists, an Ophthalmologist, a Dermatologist, and we were 25 miles away from Addenbrooks Hospital in Cambridge who supplied a steady stream of expert consultants throughout her hospital stay. When we were finally able to send her back to the US months later, she’d survived what amounted to massive burns; she was blind; she’d lost her child; she survived kidney failure and was off of peritoneal dialysis. I heard from her about a year later excited to say that she was beginning to regain some of her sight. The young general medicine officer who’d initially given her the penicillin [at her request] saw her every day over those months, and after his military service, he became an Ophthalmologist – an interest he developed while following her eye-care with the British consultants. After the fact, one never knows if this kind of maelstrom was from the original viral infection or the penicillin – both listed as possible causes in such cases. And I, for one, have never seen another such case. With an incidence of single digits per million people per year, many physicians have never seen this illness. I expect that those of us involved in this case see her every time we consider antibiotics for a sore throat or see a penicillin reaction.

Over time, I’ve come to see the two poles of drug testing and approval – efficacy and safety – as separate matters. The Randomized Clinical Trial [RCT] is good enough for efficacy if conducted correctly [de Groot style]. The Statistics and calculations of Effect Sizes can offer a reasonable place to start with clinical usage. I’m less impressed that the RCT has that same valence when it comes to safety. In fact, the FDA must agree because they require Adverse Event reporting on all subjects in all phases of all trials to be included in the New Drug Approval [NDA] submissions instead of trial-wise data. And the trials are short compared to most clinical usage. But beyond that, there are so many ways to bury the magnitude of of an Adverse Effect in the system of classification or language used eg logging suicidality in as "emotional lability" in Paxil Study 329.

In the overwhelming majority of cases, penicillin doesn’t have any effect on the course of a sore throat, whether caused by the Streptococci organisms or not. If, however, it is a Strept Throat, there was a time when the result might well be Scarlet Fever, Rheumatic Fever, Acute Glomerulonephritis – conditions that had long term and often ominous consequences. That penicillin shot has virtually eliminated those once common illnesses – a medical miracle. But the reason to get a culture to be sure it’s a Strept Throat first instead of treating all Sore Throats as Strept Throats is another kind of prevention – to minimize the possibility of cases like the one described above [among other things].

Evidence-Based Medicine is built on the model of the Randomized Clinical Trial – as if its group oriented answers dictate the practice of medicine. It’s particularly popular with people in charge of planning and policy. It gives an illusion of predictability and clarity that’s often absent in real-life clinical situations. The bell shaped curves of biology get reduced to the mean, and statistics are no longer probabilities but get treated as certainties. Guidelines that were originally derived to make sure doctors didn’t miss anything have been perverted into cost-cutting restraints or even ways to push unnecessary treatments. And the principles of preventive medicine have been coopted by a natural health industry rivaling the patent medicine hawkers of yore. RCTs were developed as tools to help physicians and patients negotiate the multivariant living case histories we share. They were never meant to be twisted and turned to market anything. But beyond that, RCTs are hardly the model for medical care itself, and are of only limited use in evaluating anything but short term safety. We all know the dangers of Anecdote-Based Medicine [and they are many], but we seem to have gone blind to its strengths…

Manufacturers have told the US Food and Drug Administration [FDA] that restricting their ability to engage in “truthful and non-misleading speech” about off-label uses of drugs and devices infringes their rights to free speech. The comments were made during hearings held in Washington, DC, on 9 and 10 of November on whether to allow manufacturers to promote drugs and medical devices for uses not approved by the FDA. Public comment on the proposal to loosen off-label promotion is open until 9 January 2017. One in every five prescriptions in the US is estimated to be for off-label use. For example, the use of certain antibiotics in children, which have been tested and approved in adults, is one commonly accepted off-label use. But manufacturers are generally prohibited from promoting off-label use, with the exception of “safe harbor” activities, such as distributing reprints of peer reviewed journal articles that may discuss unapproved uses. Industry has sued the FDA in some cases where the FDA sought to limit their off-label activities and has scored some successes in court.

Approximately 60 speakers addressed the FDA. Robert Califf, commissioner of the FDA, opened the hearings by saying that the agency had historically restricted off-label promotion to ensure the efficacy and safety of vaccines, biologics, animal and human drugs, and medical devices. He said that some off-label promotions had had “devastating consequences.” As an example, he cited the case of atypical antipsychotic drugs, which were approved for the treatment of schizophrenia and bipolar disorder, but which some companies promoted to treat dementia and behavioral problems in elderly people “using tactics that obscured the absence of reliable evidence.” He said that “subsequent clinical trials showed an increased incidence of death” among elderly people when used in this off-label manner. Califf left the door open to the need for expanded off-label promotion, however, when he said that an “evidence gap” existed for information that was not available on a product label and that additional information might help healthcare providers make better decisions for patients.

About two dozen industry representatives, surrogates, insurers, and patient groups, including Pharmaceutical Research and Manufacturers of America, the Biotechnology Innovation Organization, and the Advanced Medical Technology Association, presented after Califf. They said that discussions between industry and healthcare providers, as well as payers, about emerging uses of drugs or devices not approved by the FDA were necessary for providers to plan formularies and fee schedules, to gain information about rapid developments in medicine that do not appear on product labels, and for doctors to learn about treatments for rare conditions for which randomized controlled trials were not feasible.

Advocates of off-label promotion said that the FDA needed to loosen the levels of evidence necessary to conduct discussions with healthcare providers. John Kamp, executive director of the Coalition for Healthcare Communication, said that manufacturers should not have their arms “tied behind their back” by such restrictions. He said that the FDA’s rules were vague, and he urged the agency to allow industry to use “postapproval clinical trials … post hoc analyses, subpopulation analysis, observational data, real world evidence, and physician treatment guidelines” to support claims about off-label uses. These presenters were followed by public interest groups and patients who said that they were harmed by off-label uses of drugs and devices promoted by manufacturers…

I don’t know if they’ll publish it, but here’s the Rapid Response I submitted to the BMJ:

The FDA requires two well-conducted clinical trials demonstrating statistically significant results in favor of a drug for efficacy approval. While this is a permissive standard, the FDA at least adheres to one important element of analysis not strictly enforced by journal editors or in other venues – they require statistical separation in the declared a priori defined primary outcome variables for approval. On the other hand, this request for the FDA to "allow industry to use ‘postapproval clinical trials … post hoc analyses, subpopulation analysis, observational data, real world evidence, and physician treatment guidelines’ to support claims about off-label uses" is literally a listing of areas where efficacy has regularly been misreported using "outcome switching" among the many other methods of introducing bias. Given industry’s track record over the last several decades, it is the height of hubris to even suggest such changes.

hubris. [n.d.]. The American Heritage® Dictionary of the English Language, Fourth Edition.

They list the very mechanisms they’ve used to distort the scientific outcome of their Clinical Trials and suggest the FDA approve their legitimacy for advertising off-label drug use [in the process revealing that they know exactly what they’re doing using these illusions]…

Posted on
Monday 14 November 2016

The importance of good documentation cannot be overstated. Documentation can provide evidence of care provided or not provided; serve to promote patient safety and minimize error; ensure regulatory, accreditation, and reimbursement compliance; provide an effective defense in a medical malpractice claim, and even prevent a claim from going forward. The medical record, whether in paper or electronic form, is a legal document. The medical record is…

Considered the primary tool for communication among the psychiatrist and other care providers.

Considered an accurate reflection of the care provided.

Used to reconstruct the care provided.

Provides evidence of professional credibility.

Scrutinized by the plaintiff and defense attorneys.

Documentation includes the notes in the psychiatric medical record itself, including informed consent, telephone messages/responses, prescriptions, and, if used, email communication with the patient.

Documentation should have these characteristics:

Clear: Document using specific, factual, and objective language. Avoid language that is speculative, opines, or is subjective in nature.

Comprehensive: Document all facts relevant to the course of treatment, patient condition, and response to treatment.

Concurrent: Document as soon as possible but never in advance. If there is a late entry, label the note as such.

Credible: Document in a professional, appropriate manner. Never alter the medical record because no matter how good and appropriate the care, an altered record is indefensible.

The basic elements for documentation include the following:

A thorough medical history: Is the patient’s medical, psychiatric, and social history, as well as the family medical and psychiatric history, thoroughly documented?

Relevant information regarding diagnosis and treatment: Is the assessment, diagnosis, and treatment plan recorded for each patient visit? Is there evidence of recognition and timely interventions upon a change in the patient’s condition? Are telephone messages and the responses documented with dates and times? If the patient’s insurer audits the medical record, will the documentation support the billing practices?

Assessment of the patient’s risk for suicide or possible violence toward others: Is the risk of suicide or violence toward others assessed and addressed throughout treatment?

Informed consent: Is there documentation that consent was obtained from the patient at the start of treatment? When new medications were started?

Medications: Are the medication prescriptions complete with medication name, dosage, and frequency? Is there evidence that side effects are consistently monitored, including blood levels as appropriate? If a medication is used off-label or carries a black-box warning, manufacturer’s warning, or FDA advisory, is the documentation explicit regarding discussion of the potential benefits, risks, side effects, and alternatives?

Compliance or noncompliance with treatment: Is the description of the patient’s compliance to the treatment plan, medications as ordered, and follow-up care noted in an objective manner without labeling?

Formal consultations: Is the consultation with another provider, including the specifics regarding the patient’s diagnosis and treatment, the reason for the consultation, the name of the consultant, and recommendations, recorded in the notes?

Document thoroughly and concisely. Failure to document is not only unethical but can lead to license revocation, restriction, or disciplinary actions and also the inability to defend a malpractice claim.

Allied World, through its subsidiaries, is a global provider of innovative property, casualty and specialty insurance and reinsurance solutions. Allied World is the APA-endorsed carrier for the professional liability program through its strategic relationship with the American Professional Agency Inc., the Program Administrator. This information is provided as a risk management resource and should not be construed as legal, technical, or clinical advice. Consult your professional advisors or legal counsel for guidance on issues specific to you. This material may not be reproduced without the permission of Allied World. Risk management services are provided by or arranged through AWAC Services Co., a member company of Allied World. Anne Huben-Kearney, R.N., B.S.N., M.P.A., is assistant vice president of the Psychiatric and Healthcare Risk Management Group of AWAC Services Company, a member company of Allied World.

Medicine changed during my time in grade, more than I could’ve ever dreamed half a century ago when I graduated from medical school. When people say things like that, they’re usually talking about the scientific advances. At the time I was an Intern, we were just begining to realize that patients died from arrhythmias in the period just after a heart attack and had begun to monitor the EKG – a major advance. Now there’s a monitor in every hospital room, but in the period just after a heart attack, the patients don’t go to their rooms. They usually go to a cath lab for a stent that opens the clogged artery [often for good].

But those changes were predictable. Medical science regularly marches upward. The changes I’m talking about are things like this article from the PSYCHIATRICNEWS focusing on Risk Management. Fifty years ago, had you handed me an article about Risk Management, I would’ve been curious to know what it was about – assuming that it would be about the risk patients faced from their diseases, or maybe their treatments. It wouldn’t have ever occurred to me that it would be about managing he doctors’ risk from the patients. In the first paragraph of the article where it gives the rationale for this kind of documentation, it mentions promote patient safety and minimize error in passing, but most of it is about preemptively heading off charges of negligence and/or malpractice. And it ends with Failure to document is not only unethical but can lead to license revocation, restriction, or disciplinary actions and also the inability to defend a malpractice claim – suggesting that one should Provides evidence of professional credibility in every note.

I suppose the suggestion that this kind of micro-documentation might make sense if the time allotted for a patient visit included the time it takes to write this kind of note, but that’s not the case. And we might add in the use of an Electronic Medical Record [EMR] system built to contain all of this information [most of which don’t have psychiatry in mind]. And perhaps others are more comfortable than I am being a clinician who is looking primarily at a computer screen. But those are just a few examples of the ground clutter choking medical practice. There are plenty of other things – things like screening [BP, P, PHQ-9, etc.].

As a free clinic staffed by retirees with only one paid employee [the Director], our little clinic was a great place to work even though we operated on a wing, a prayer, donated and generic drugs, and old people. Then came the decision to take insurance from those that had it – to get certified. Over the last year, the volunteer physicians, nurses, pharmacists, etc have all left [except for me] – and I’m finally mustering my way out over the next 3 or 4 months. It has been heartbreaking to see things change so quickly in spite of the well-meaning powers that be who tried to keep it from happening. I naively thought I could Ostrich my way through it, but I can’t bring it off in spite of trying.

And, by the way, being asked to give evidence of professional credibility in case of a lawsuit in every note takes time away from actually being professionally credible…

Posted on
Sunday 13 November 2016

We live in an age of Meta-Analyses and Systematic Reviews [studies of studies]. Some, like watchdog John Ioannidis, lament their frequency as redundant and/or unnecessary [The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses]. But at least in the domain of neuroscience, I see these meta-analyses as an attempt at oversight in an area where advanced technologies have been applied to clinical problems without yielding much in the way of clarity. An example:

Importance During the past 20 years, numerous neuroimaging experiments have investigated aberrant brain activation during cognitive and emotional processing in patients with unipolar depression [UD]. The results of those investigations, however, vary considerably; moreover, previous meta-analyses also yielded inconsistent findings.

Study Selection Neuroimaging experiments [using fMRI or PET] reporting whole-brain results of group comparisons between adults with UD and healthy control individuals as coordinates in a standard anatomic reference space and using an emotional or/and cognitive challenging task were selected.

Data Extraction and Synthesis Coordinates reported to show significant activation differences between UD and healthy controls during emotional or cognitive processing were extracted. By using the revised activation likelihood estimation algorithm, different meta-analyses were calculated.

Main Outcomes and Measures Meta-analyses tested for brain regions consistently found to show aberrant brain activation in UD compared with controls. Analyses were calculated across all emotional processing experiments, all cognitive processing experiments, positive emotion processing, negative emotion processing, experiments using emotional face stimuli, experiments with a sex discrimination task, and memory processing. All meta-analyses were calculated across experiments independent of reporting an increase or decrease of activity in major depressive disorder. For meta-analyses with a minimum of 17 experiments available, separate analyses were performed for increases and decreases.

Conclusions and Relevance Inconsistencies exist across individual experiments investigating aberrant brain activity in UD and replication problems across previous neuroimaging meta-analyses. For individual experiments, these inconsistencies may relate to use of uncorrected inference procedures, differences in experimental design and contrasts, or heterogeneous clinical populations; meta-analytically, differences may be attributable to varying inclusion and exclusion criteria or rather liberal statistical inference approaches.

This meta-analysis focuses on neuroimaging studies of patients where DSM/ICD criteria were used to define the target cohort of depressed subjects. While this classification has survived for now 36 years, I know of no evidence that these criteria define anything like a discrete clinical entity.

Criteria Related to the Investigation Participants Included experiments statistically contrasted neural activation between an adult [>18 years] UD group [based on DSM-IV-TR and DSM-5 or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision] and a group of healthy controls…

The studies examined were ones that compared brain activity measured by PET scans or fMRI studies between their depressed cohort and normals. That presumes a hypothesis that the experimental subjects would have something detectable in their brains either causing or as a result of their depression. Thus there were two bedrock assumptions: [1] a unitary clinical entity [2] that has something to do with the brain.

Müller et al provide a technically sophisticated and informative set of meta-analyses examining altered brain activity in adults with symptomatic unipolar depression. The striking overall finding of their analyses is the lack of consistent group differences across studies. The absence of replicable effects across studies remained even when they addressed a number of potentially key confounds, such as examining only patients not receiving medication, patients without comorbidities, and patients without late-life or geriatric depression…

Don’t think that reading this blog post is the definitive take on this comprehensive and complex meta-analysis. Read the article and its supplements. What you’ll find is a window into the heavy duty math and numerous assumptions that go into these neuroimaging studies. What the article says is that we don’t know anything about the altered brain activity in unipolar depression. Reading this, I’m not even sure that we know if there is any altered brain activity in unipolar depression. The random scattering of hot and cold spots from the studies along with the dramatically insignificant p-values isn’t much of a confidence builder. The authors give a laundry list of possible reasons for the non-replicability and non-convergence, suspecting that methodological problems top the list. I would start my own list at the input end of things and quote historian Edward Shorter from Before Prozac:

"Bottom Line: Major Depression doesn’t exist in Nature. A political process in psychiatry created it…"

Major Depressive Disorder, Unipolar Depression, hasn’t played out as an entity, it’s a symptom complex [see which nail?…]. Is it a brain disease? So far, there’s some indirect evidence that there are perhaps several biological entities in the mix in small doses [Melancholia, Depressive Episodes in Manic Depressive Illness], and who knows what else? The point being that there may be methodological problems with these neuroimaging studies, sure enough. But that aside, the questionable diagnostic and etiological speculations before they even turn on the MRI machine are probably more to the point. I would venture that a strong possibility to be considered is that they’re chasing a biomedical etiology in a heterogeneous population of people with a symptom complex primarily generated in the biographical and psychosocial domain of living…

Posted on
Sunday 6 November 2016

At least for the moment, the polls seem to be leveling out a bit …

… and I found myself able to think [briefly] about other things. And the other thing on the front burner was a decision I made last week After eight years volunteering at a rural charity clinic, I’ve decided to wind things down and retire for good. If it were for age or health considerations, I wouldn’t be mentioning it. But that’s not the reason.

Our area has a number of retirement communities. At some point, a few retired physicians opened a free clinic for the uninsured, staffed by an army of retired volunteers with a wide variety of medical skills. They raised the money with golf tournaments and donations, and created something I thought was unique – an interface between the retirees [from the "1%" retirement communities] and the patients from the other end of the financial spectrum. But with the coming of the national effort for universal insurance, the powers-that-be decided to change the clinic. We would still see the remaining uninsured, but collect the insurance reimbursement from those who were insured. And so we have a new building replacing our old "trailers." It’s staffed now by employees with far fewer volunteers. We have added Electronic Medical Records [EMR] and a jillion other trappings of a clinic that has been "certified" to receive the insurance "payments."

Working there was a major change from my urban referral psychotherapy practice – more back to basics. The patients often had grown up pillar to post, exposed to abusive situations, substance abuse, and other craziness. At first, I was horrified at the medicine regimens people were on [almost everyone was "on" something]. The focus of this blog arose out of my explorations of these alarming medication practices. So the first order of business was to deal with the medication quagmires. Since I was the only act in town, I was also a social worker, an addiction counselor, a "common sense" psychotherapist, a medication manager, a neurologist, a grief counselor, etc – literally, a jack of many trades. Over time, I got my rhythm and found that I was able to do a lot more for patients in this setting than I might have ever imagined – even with infrequent contact.

I guess I thought I could ignore the changes that came with our new status, but I can’t. Instead of a brief written note and handwritten prescriptions, I have to do it on a computer using a system designed by someone who cut class on the day they taught "user friendly." Apparently the system pays extra if there’s a vital signs recorded with every visit, and a waiting room PHQ-9. There are frequent knocks on the door for some procedural something-or-another. Absolutely everything is just so much harder, and I’m sure that I now spend more than half my time doing these administrative, documentation tasks. The long and short of it is, instead of doing what I know how to do, I spend my time doing things that I don’t know how to do [and see no reason to be doing].

I could mount a reasonably convincing argument that the coming of "the system" with its rules and procedures makes it impossible for me to do my job, but that’s not really why I decided to muster out. I just can’t find a way not to be constantly pissed off. At times I think things like "a leopard can’t change its spots" or "you can’t teach an old dog new tricks," but most of the time, I think they’ve really messed up something that was working just fine, and I just don’t want to do it "their way" [whoever they are]. It’s as simple as, if you’re willing to work for free, and you’re 75 years old, you ought to be able to do it "your way." Obviously, the other side of the coin is that I’ll be abandoning the patients and that has weighed heavily, so I’m sticking around for a while to give the clinic time to get something else in place. I feel sad, but also relieved..

Posted on
Thursday 3 November 2016

BACKGROUND: We explore whether the number of null results in large National Heart Lung, and Blood Institute [NHLBI] funded trials has increased over time.

METHODS: We identified all large NHLBI supported RCTs between 1970 and 2012 evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease. Trials were included if direct costs >$500,000/year, participants were adult humans, and the primary outcome was cardiovascular risk, disease or death. The 55 trials meeting these criteria were coded for whether they were published prior to or after the year 2000, whether they registered in clinicaltrials.gov prior to publication, used active or placebo comparator, and whether or not the trial had industry co-sponsorship. We tabulated whether the study reported a positive, negative, or null result on the primary outcome variable and for total mortality.

RESULTS: 17 of 30 studies [57%] published prior to 2000 showed a significant benefit of intervention on the primary outcome in comparison to only 2 among the 25 [8%] trials published after 2000 [χ2=12.2, df= 1, p=0.0005]. There has been no change in the proportion of trials that compared treatment to placebo versus active comparator. Industry co-sponsorship was unrelated to the probability of reporting a significant benefit. Pre-registration in clinical trials.gov was strongly associated with the trend toward null findings.

CONCLUSIONS: The number NHLBI trials reporting positive results declined after the year 2000. Prospective declaration of outcomes in RCTs, and the adoption of transparent reporting standards, as required by clinicaltrials.gov, may have contributed to the trend toward null findings.

Kind of a cute and telling study. The National Heart Lung, and Blood Institute plotted the standardized outcome [Relative Risk of the Primary Outcome] against the year of the study for all their funded studies from 1970 to 2014. Look what happened when ClinicalTrials.gov came along in 2000 and they started preregistering their Primary Outcome Variables a priori. Made honest scientists out of them! Speaking of cute, the article that pointed me to it said, "Preregistration of clinical trials causes medicines to stop working!"

Posted on
Thursday 3 November 2016

I’m not much of a sports fan, but last night was fun and a major relief from Election Fatigue Syndrome – so I pass on a few more in case the next five days are getting to you like they tend to get to me…

VIENNA – Janneke A. Bastiaansen, PhD, has some advice for clinicians and researchers as they peruse the published literature on clinical trials of medication or psychotherapy for major depressive disorder: Don’t believe everything you read. “Be critical. Use your critical mind,” she urged at the annual congress of the European College of Neuropsychopharmacology.

The results of her analysis of 105 clinical trials of antidepressant drugs and 142 studies of psychotherapy indicated that the literature is rife with four types of bias: publication, outcome reporting, spin, and citation bias. “The quality of the evidence base is vital. We base our clinical decisions on what’s out there in the literature. And I think it’s really important to know that there are various biases that can color the literature,” said Dr. Bastiaansen, a psychologist at the University of Groningen, the Netherlands.

She took a closer look at 105 clinical trials of antidepressant drugs registered with the U.S. National Institutes of Health at clinicaltrials.gov. Fifty-three reported positive findings, and 52 were negative. Fifty-two of the 53 positive trials were ultimately published, as were only 25 of the 52 negative studies. That’s a sterling example of publication bias.

Upon careful scrutiny of the 25 negative trials that were published, 10 were misleadingly reported as positive studies. The investigators either switched out the prespecified primary outcome previously filed with NIH and promoted a positive secondary outcome to primary outcome status because the original primary outcome was negative, or they omitted the negative outcomes altogether. That’s outcome-reporting bias. Of the 15 published negative drug trials that were free of outcome-reporting bias, the authors of 10 of the studies employed “spin,” using phrases such as “the treatment was numerically superior.” Thus, only 5 of the 25 published negative clinical trials unambiguously reported that the studied treatment was not effective.

“Here the message is that, when you read a paper, look at the results, come up with your own conclusion, and then compare it with the conclusion of the authors, because sometimes they’ve colored it in a more positive way,” Dr. Bastiaansen said in an interview. Citation bias is the phenomenon whereby positive clinical trials are cited more frequently than published negative trials. “As a clinician, if you look at the literature and print out every paper that’s out there on a given antidepressant drug for major depression, and you look at that pile, you’ll think: ‘Ah, the literature is really strong about this treatment effect,’ because positive papers selectively cite other positive papers,” she continued.

,,, and psychotherapy?

The pharmaceutical industry takes a lot of heat for selectively burying company-sponsored negative trials, but the literature on psychotherapy for major depression is actually more opaque. “A lot of people aim their arrows at the pharmaceutical industry and say: ‘Everything’s bad about pharma,’ but actually, you see bias in every field. You see it in the trials of psychotherapy. It’s very important to know that it’s ubiquitous. The positive side of the antidepressant drug trials is that there’s this standard database [clinicaltrials.gov], and you can use it to check out what trial is published and what’s not. It’s not the case for psychotherapy trials. I think we need a mandatory registry for clinical trials of psychotherapy as well,” Dr. Bastiaansen said. Of the 142 psychotherapy studies, 49 were negative, but the abstracts of only 12 of those 49 concluded that psychotherapy was not more effective than a control.

One wonders how many such papers we have to hear before we get their messages. Here’s another – this time harms [abstract only]:

Objective: To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder.

Setting: Published trials identified by searching PubMed and Embase and clinical study reports obtained from the European and UK drug regulators.

Participants: Double-blind, placebo-controlled trials in adult healthy volunteers that reported on suicidality or violence or precursor events to suicidality or violence.

Results: A total of 5787 publications were screened and 130 trials fulfilled our inclusion criteria. The trials were generally uninformative; 97 trials did not report the randomisation method, 75 trials did not report any discontinuations and 63 trials did not report any adverse events or lack thereof. Eleven of the 130 published trials and two of 29 clinical study reports we received from the regulatory agencies presented data for our meta-analysis. Treatment of adult healthy volunteers with antidepressants doubled their risk of harms related to suicidality and violence, odds ratio 1.85 [95% confidence interval 1.11 to 3.08, p = 0.02, I² = 18%]. The number needed to treat to harm one healthy person was 16 [95% confidence interval 8 to 100; Mantel-Haenszel risk difference 0.06]. There can be little doubt that we under- estimated the harms of antidepressants, as we only had access to the published articles for 11 of our 13 trials.

Conclusions: Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence.

An Aside: this second paper gets at something we tried to show in our Study 329 Continuation Phase paper. Here they list a group of suicidality precursors. Sometimes it’s called akathisia. In my mind, I call it Agita. It’s an uncomfortable experienced not-me-ness, not-right-ness, described by patients in many different ways, and it’s closely linked to the violence that sometimes follows. I think it’s more common than we know, bewcause many patients just say "this medicine’s not for me" and stop it [and we just don’t hear about it]. Later, they say, "Oh, I just can’t take that stuff!

Matching the Industry of CROs and Ghost -management and -writing enterprises, there’s almost an academic-specialty growing to deconstruct these jury-rigged clinical trial reports that have descended on our literature like a hoard of locusts – particularly the psychiatric literature. Dr. Bastiaansen in the first paper gives some really good advice, however she’s speaking at a meeting of specialists and scientists, not the primary care physicians who are prescribing the medicines. I now do everything she says – look up the drugs in ClinicalTrials.gov checking for publication bias, look carefully for evidence of outcome switching, am ever alert to spin. But I’m not normal. It’s almost my new career/hobby/obsession. As a practicing doctor, no way would I be able to take the time to do that. I’d be lucky to have time to read the abstracts, much less the whole articles, way much less than look them up on ClinicalTrials.gov or Drugs@FDA.

Articles like these are part of a great big wake-up call, and I’m not sure they’re reaching the right audience in the right ways. For the moment, I’ll just add them to the growing catalog, and pick back up next week after the national election is behind us. Right now, diversion time – World Series, Game 7!